Abstract：
OBJECTIVE: Primary effusion lymphoma (PEL) is classified as a rare non-Hodgkin\'s B-cell lymphoma that is caused by Kaposi\'s sarcoma-associated herpesvirus (KSHV); PEL cells are latently infected with KSHV. PEL is frequently resistant to conventional chemotherapies. Therefore, the development of novel therapeutic agents is urgently required. Nigericin, a H+ and K+ ionophore, possesses unique pharmacological effects. However, the effects of nigericin on PEL cells remain unknown.
METHODS: We examined the cytotoxic effects of the K+ ionophores, nigericin, nonactin, and valinomycin, on various B-lymphoma cells including PEL. We also evaluated ionophore-induced changes in signaling pathways involved in KSHV-induced oncogenesis. Moreover, the effects of nigericin on mitochondrial membrane potential and viral reactivation in PEL were analyzed.
RESULTS: Although the three tested ionophores inhibited the proliferation of several B-lymphoma cell lines, nigericin inhibited the proliferation of PEL cells compared to KSHV-negative cells. In PEL cells, nigericin disrupted the mitochondrial membrane potential and caused the release of cytochrome c, which triggered caspase-9-mediated apoptosis. Nigericin also induced both an increase in phosphorylated p38 MAPK and proteasomal degradation of β-catenin. Combination treatment of nigericin with the p38 MAPK inhibitor SB203580 potentiated the cytotoxic effects towards PEL cells, compared to either compound alone. Meanwhile, nigericin did not influence viral replication in PEL cells.
CONCLUSIONS: Nigericin induces apoptosis in PEL cells by mitochondrial dysfunction and down-regulation of Wnt/β-catenin signaling. Thus, nigericin is a novel drug candidate for treating PEL without the risk of de novo KSHV infection.
METHODS: We examined the cytotoxic effects of the K+ ionophores, nigericin, nonactin, and valinomycin, on various B-lymphoma cells including PEL. We also evaluated ionophore-induced changes in signaling pathways involved in KSHV-induced oncogenesis. Moreover, the effects of nigericin on mitochondrial membrane potential and viral reactivation in PEL were analyzed.
RESULTS: Although the three tested ionophores inhibited the proliferation of several B-lymphoma cell lines, nigericin inhibited the proliferation of PEL cells compared to KSHV-negative cells. In PEL cells, nigericin disrupted the mitochondrial membrane potential and caused the release of cytochrome c, which triggered caspase-9-mediated apoptosis. Nigericin also induced both an increase in phosphorylated p38 MAPK and proteasomal degradation of β-catenin. Combination treatment of nigericin with the p38 MAPK inhibitor SB203580 potentiated the cytotoxic effects towards PEL cells, compared to either compound alone. Meanwhile, nigericin did not influence viral replication in PEL cells.
CONCLUSIONS: Nigericin induces apoptosis in PEL cells by mitochondrial dysfunction and down-regulation of Wnt/β-catenin signaling. Thus, nigericin is a novel drug candidate for treating PEL without the risk of de novo KSHV infection.
摘要：
目的：原发性渗出性淋巴瘤（PEL）被归类为一种罕见的非霍奇金B细胞淋巴瘤，由卡波西肉瘤相关疱疹病毒（KSHV）引起；PEL细胞潜伏感染KSHV。PEL通常对常规化疗有抗性。因此,迫切需要开发新的治疗剂。Nigericin,H+和K+离子载体，具有独特的药理作用。然而,尼日利亚霉素对PEL细胞的影响尚不清楚.
方法：我们检查了K+离子载体的细胞毒性作用，Nigericin,nonactin,和缬氨酸霉素,包括PEL在内的各种B淋巴瘤细胞。我们还评估了离子载体诱导的与KSHV诱导的肿瘤发生有关的信号通路的变化。此外，分析了尼日利亚霉素对PEL线粒体膜电位和病毒再激活的影响.
结果：尽管三个测试的离子载体抑制了几种B淋巴瘤细胞系的增殖，与KSHV阴性细胞相比，nigericin抑制PEL细胞的增殖。在PEL细胞中,尼格林破坏线粒体膜电位，并引起细胞色素c的释放，这触发了caspase-9介导的细胞凋亡。Nigericin还诱导磷酸化p38MAPK的增加和β-catenin的蛋白酶体降解。nigericin与p38MAPK抑制剂SB203580的联合治疗增强了对PEL细胞的细胞毒性作用，与单独的任何一种化合物相比。同时,尼日利亚霉素不影响PEL细胞中的病毒复制。
结论：Nigericin通过线粒体功能障碍和Wnt/β-catenin信号下调诱导PEL细胞凋亡。因此，Nigericin是治疗PEL的新型候选药物，没有从头KSHV感染的风险。
方法：我们检查了K+离子载体的细胞毒性作用，Nigericin,nonactin,和缬氨酸霉素,包括PEL在内的各种B淋巴瘤细胞。我们还评估了离子载体诱导的与KSHV诱导的肿瘤发生有关的信号通路的变化。此外，分析了尼日利亚霉素对PEL线粒体膜电位和病毒再激活的影响.
结果：尽管三个测试的离子载体抑制了几种B淋巴瘤细胞系的增殖，与KSHV阴性细胞相比，nigericin抑制PEL细胞的增殖。在PEL细胞中,尼格林破坏线粒体膜电位，并引起细胞色素c的释放，这触发了caspase-9介导的细胞凋亡。Nigericin还诱导磷酸化p38MAPK的增加和β-catenin的蛋白酶体降解。nigericin与p38MAPK抑制剂SB203580的联合治疗增强了对PEL细胞的细胞毒性作用，与单独的任何一种化合物相比。同时,尼日利亚霉素不影响PEL细胞中的病毒复制。
结论：Nigericin通过线粒体功能障碍和Wnt/β-catenin信号下调诱导PEL细胞凋亡。因此，Nigericin是治疗PEL的新型候选药物，没有从头KSHV感染的风险。
